CS235078B2 - Method of tetrahydro-2h-benzo-(lc)ppyrrole preparation - Google Patents

Abstract

Title compds.≮I; R1 = H, R2; R2 = allyl, Me, Et, N-Pr; Am = N(R2)2≉, useful in the treatment of Parkinsonism and in dopamine potentiation, were prepd. from V. Thus, 15.5 g 4-acetamidocyclohexanone was treated with Me2NCH(OMe)2 to give the (aminomethylene) cyclohexanone, which cyclized with H2NCH2 cook and was acetylated to give I.

Description

The present invention relates to a process for the preparation of substituted DL-4,5,6,7-tettahydro-2H-benzo [c] pyrroles of the formula I

where

R1 is hydrogen or methyl,

Am is N (R ² ) 2, wherein R ² 'is. methyl, ethyl or n-propyl, and pharmaceutically acceptable salts thereof, characterized in that DL-5-amino-4,5,6,7-tetrahydro-2H-4-amino-4-amino-4,5-dihydro-2H-pyrrole of formula V

reacted with a saturated aldehyde of up to 3 carbon atoms and then reduced with an alkali metal hydride to form a compound of formula I wherein R ¹ is hydrogen. and Am is a substituent -N (R ²⁾ wherein R ² is as defined above, whereupon the product obtained by reaction with a methyl halide and a base, optionally converting the compound of formula I wherein R1 is methyl and Am is N (R 2) 2 wherein R ² is as defined above, and optionally converted compounds of formula I to their pharmaceutically acceptable salts.

The compounds of formula I are useful as dopamine agonists and can also be used for the treatment of Parkinson's syndrome and as prolactin inhibitors.

Pharmaceutically acceptable salts of the compounds of formula I include salts derived from non-toxic inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphoric acid and the like, as well as salts derived from non-toxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic acids. and aliphatic dicarboxylic acids, aromatic acids, aliphatic and aromatic sulfonic acids and others. Such pharmaceutically acceptable salts include sulfates, pyrosulfates, hydrogen sulfates, sulfites, hydro-235078 sulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, propionates, isobutyrates, caprates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleate, butin-1,4-dioates, hexin-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, hydroxybenzoates, m-ethoxybenzoates, m-ethoxybenzoates phthalates, terephthalates, benzenesulfonates, toluenesulfonates, chlorobenzenesulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, malate, tartrates, methanesulfonates, propanesulfonates and naphthalene sulfonates, naphthalene sulfonates .

While the compounds of formula I have been named as 4,5,6,7-tetrahydro-2H-benzo [3,2-b] pyrroles, an alternative name for these compounds as 4,5,6,7-tetrahydroisoindoles can also be used.

The presence of a substituent on the carbon atom of the 5-benzo [c] pyrrole or isoindole ring provides a center of asymmetry to these molecules. The compounds of formula I include two optical isomers occurring as the DL-pair or racemate. Resolution of the DL-pair of formula I to the optical antipodes can be carried out by known methods.

The invention is illustrated by the following examples.

Example A

Preparation of DL-5-amino-4,5,6,7-tetrahydro-2H-biphenyl-pyrrole

From 15.5 g of 4-acetamidocyclohexanone (prepared according to the method of Fraser and Swingle Can. J. Chem. 48, 2065 (1970)) was prepared a reaction mixture with 80 g of dimethylformamide dimethyl acetal, 1.5 ml of triethylamine and 500 ml of benzene. Benzene was distilled off for 1.5 hours so that the total volume was reduced to about 1/2 of the original volume, then an additional 250 ml of benzene was added and the reaction mixture was heated to just below boiling for two hours, then distilled again until half of the original volume remained. (250 mL) The above procedure is repeated once more except that the original volume is reduced to one-third of the original volume (167 mL), then the reaction mixture is cooled and filtered The filter cake consists of DL-4-acetamido-2. -dimethylaminomethylenecyclohexanone formed by the above reaction, yield 6.45 g. Evaporation of the filtrate to dryness gave a residue which was chromatographed in chloroform to 200 g of florisil (trademark of activated silica). Magnesium stearate, which is a hard porous, granular substance described in US Patent No. 2,393,625), a mixture of chloroform with increasing amounts of methanol (0-5%) as eluent provides additional DL-4.

acetamido-2-dimethylaminomethylene-cyclohexanone, m.p. 132-133 ° C (from benzene), yield 5.55 g total yield 12 g.

Analysis:

calculated:

% C, 62.83;% H, 8.63. 13,32 θ / ο N, found:

H, 8.38; N, 13.12.

Potassium glycinate is prepared by reaction of 9 g of glycine and 6.7 g of potassium hydroxide in 400 ml of anhydrous ethanol. 22.6 g of DL-4-acetamido-2-dimethylaminomethylenecyclohexanone were added thereto, and the resulting mixture was heated to boiling under a nitrogen atmosphere for 1.75 hours. The reaction mixture was cooled, diluted with ether and filtered. Filter cake. Weight

28.7 g was added to 400 ml of acetic anhydride and the resulting reaction mixture was heated under reflux for one hour. The reaction mixture was cooled and the volatiles were evaporated in vacuo. The resulting residue was suspended in chloroform and filtered. The filtrate is chromatographed on 350 g of florisil. using chloroform containing increasing amounts of (0-2%) methanol as eluent. Fractions containing DL-2-acetyl-5-acetamido-4,5,6,7-tetrahydro-2H-benzo [c] pyrrole as defined by the above reaction were combined according to thin layer c-chromatography. and the solvent was evaporated. Crystallization of the residue from ether gave purified DL-2-acetyl-5-acetamido-4,5,6,7-tetrahydro-2H-benzo [c] pyrrole, m.p. 151-153 ° C, yield 17.7 g.

Analysis: calculated:

% C, 65.43;% H, 7.32;% N, 12%

H, 7.34; N, 12.45.

The hydrolysis mixture was prepared from 5.1 g of DL-2-acetyl-5-acetamido-4,5,6,7-tetrahydro-2H-benzo [c] pyrrole, 50 g of sodium hydroxide, 50 ml of water and 200 ml of ethanol. The mixture was heated to boiling under nitrogen for 16 hours and then cooled. The cooled mixture was diluted with water. The alkaline aqueous mixture was extracted several times with methylene chloride and the combined organic extracts were washed with saturated aqueous sodium chloride solution and dried. Evaporation of the solvent gave the residue containing DL-5-amino-4,5,6,7-tetrahydro-2H-beezo [c] pyrrole formed by the above reaction. The chloroform solution of the residue was filtered through 105 g of alumina (activity II). Concentration of the resulting filtrate gave 2.52 g of a yellow solid containing DL-5-amino-4,5,6,7-tetrahydro-2H-benzo [c] pyrrole.

ExamplesΒ

Preparation of DL-5-acetamido-4,5 _} 6,7-tetrahydro-2H-benzo [c] pyrrole

To a solution of 6.7 g of 4-acetamidocyclohexanotine (prepared according to the method of Fraser and Swingl, Can. J. Chem, 48, 2065 (1970)) in 150 ml of anhydrous ethanol is added 25 ml of ethyl chloroformate containing several crystals of p-toluenesulfonic acid monohydrate. The reaction mixture was stirred at room temperature for 16 hours, then the volatiles were removed in vacuo, the residue containing diethyl ketal was dissolved in 200 ml of toluene, and the toluene was distilled off under nitrogen until all of the diethyl ketal was converted to the 1-ethoxycyclohexene derivative. Evaporation of toluene gave a residue consisting of 4-acetamido-1-ethoxycyclohexene, mp 100-102 ° C after recrystallization from ether / hexane (6.2 g).

A solution of 3 g of 4-acetamido-ethoxy-ethoxyxycyclohettene in 40 ml of dioxane is slowly added to a solution of 3.2 g of 1,2,4,5-tetrazazicicarboxylic acid ester (prepared according to Sauer et al. Chem. Ber. 98, 1435). (1965)] in 100 ml dioxane The reaction mixture was stirred at room temperature for 3 days, after which time one main spot and several minor stains were present in thin layer chromatography, and the reaction mixture was evaporated in vacuo. of chloroform, the chloroform solution is chromatographed on 200 g of fiorisil using an increasing amount (2 to 5%) of methanol as the eluent.The fractions, which, according to thin layer chromatography, contain one major spot, are combined and the solvent is evaporated from the combined fractions. The residue was crystallized by trituration with ether to give the product, mp 137-138 ° C, yield 3.21 g. Crystallization of the residue from a mixture of ether and methanol gave Purified D 6 -tacetamclo-1 H -di (carbomethoxy) -5,6,7,8-tetrahydrobenzo [c] pyridazine m.p. 143-144 ° C.

Analysis:

calculated:

4.72% C, 5.58% H, 13.67 ° / o N, found:

% C, 54.75;% H, 5.64;% N, 13.49.

By adding 2.59 g of DL-t-octamido-1,4-di (carbomethoxy) -5,6,7,8-tetrahydrobenzo [d] pyridazine to 100 ml of glacial acetic acid, a solution is prepared to which 5 g of zinc are added. The mixture was stirred at room temperature for 1 day. After stirring for 6 hours, an additional 5 g of zinc was added. Unreacted zinc dust is then removed by filtration of the reaction mixture and the resulting filtrate is poured onto ice. The filtrate was basified with 14 N aqueous ammonium hydroxide, and the alkaline mixture was extracted several times with a mixture of chloroform and isopropyl alcohol. The organic extracts were separated and combined. The combined extracts were washed with a saturated aqueous sodium chloride solution and then dried. Evaporation of the solvent gave DL-5-acetonitrile-1,3tdi (carbomethoxy) -4,5,6,7-tetrahydro-2H-benzo ^[ c] pyrrole. Yield = 1.83 g. Crystallization from methanol gave a melting point. Mp 231-232 ° C.

Analysis:

calculated:

% H, 6.16;% N, 9.52.

H, 5.99; N, 9.26.

The reaction mixture was prepared from 1.8 g of D-tacetamido-l, 3-di (carbomethoxy) -4,5,6,7-tetrahydro-2Htbenzo _^[j c] pyrrole, 80 ml of tetrahydrofuran and 20 ml of 2N aqueous sodium hydroxide sodium. The reaction mixture was heated under nitrogen for about 3 hours, cooled, and the volatiles evaporated in vacuo. The residue is dissolved in 25 ml of water and the aqueous solution is acidified by the addition of 1 N aqueous hydrochloric acid.

The resulting DL-5-acetic Acid 1,3,3-dihydroxy-4,5,7-tetrahydro-2H-bentazo [c] pyrrole is insoluble in the acid phase and precipitates and is collected by filtration. Crystallization from benzene / methanol gave a crystalline diacid, m.p. 233-235 ° C (dec.).

Analysis:

calculated:

54.13% C, 5.30% H, 10.52% N, loaded *

H, 5.37; N, 10.45.

Reaction mixture prepared from 850 mg of DLt5t-acetamido-1,3'-dicarboxy-4,5,6,7-tetrchydro-2H-benzo [c] pyrrole, 50 mg of powdered copper and 25 ml of quinoline was heated to 200 ° C. in a nitrogen atmosphere. When the temperature reaches 150 ° C, gas evolution is observed. The reaction mixture was heated to 200-210 ° C for 15 minutes, then poured onto ice. The resulting aqueous mixture was extracted with chloroform and the chloroform extract was separated, washed with 0.1 N aqueous hydrochloric acid, 10% aqueous sodium hydroxide, and finally water. The chloroform was evaporated in vacuo to give 0.26 g of a dark oily residue. Chromatography on 15 g of fiorisil using chloroform with 0 to 1% methanol as eluent gave 40 mg of DLt5t-Cetyl-4,5,6,7-tetrchydolo-2Htbenzo [c] pyrrole. The product is identical to the compound prepared by deacylation of DL-5-acetamido-2-acetyl-4,5,6,7-tetrahydr o-2H-benzo [c] pyrrole according to Example A.

End products

Example 1

Preparation of DL-5-diethylamino-4,5,6,7-tetrahydr o-2H-benzo [c] pyrrole

By adding 2.52 g of DL-5-amino-4,5,6,7-tetrahydro-2H-benzo [c] pyrrole prepared in Example A to 100 ml of methanol, a solution is prepared to which 1.2 g of sodium cyanoborohydride is added. and then 6 ml of acetaldehyde. The reaction mixture was stirred at room temperature under nitrogen for 16 hours and then diluted with aqueous sodium bicarbonate. The aqueous phase is extracted with chloroform, the chloroform extract is separated and washed with a saturated aqueous sodium chloride solution. The chloroform solution was then dried and the solvent was evaporated. The resulting residue was redissolved in chloroform and the chloroform solution was chromatographed on 35 g of florisil using chloroform containing increasing amounts of 2-4% methanol as eluent. The fractions combined according to thin layer chromatography contain a material different from the starting material; 1.84 g of the solid thus obtained are chromatographed again on florisil. The fractions containing DL-5-diethylamino-4,5,6,7-tetrahydro-2H-benzo [c] pyrrole according to thin layer chromatography were combined and the solvent was evaporated in vacuo from the combined fractions. A residue of 0.66 g is obtained. The residue is dissolved in ether and treated with an excess of ethereal maleic acid solution. The thus prepared DL-5-diethylamino-4,5,6,7-tetrahydro-2H-benzo [c] pyrrole maleate is recrystallized from methanol-ether to give the purified product, m.p. 81-83 ° C, yield = 385 mg.

Analysis:

calculated:

% C, 62.32;% H, 7.84;% N, 9.08%.

% C, 62.37;% H, 7.57;% N, 8.94.

Example 2

Preparation of DL-5-di-n-propylamino-4,5,6,7-tetrahydro-2H-benzo [c] pyrrole

Following the procedure of Example 1, but substituting propionaldehyde for acetaldehyde, DL-5-di-n-propylamino-4,5,6,7-tetrahydro-2H-benzo [c] pyrrole maleate was prepared, m.p. 134-136 ° C, after crystallization. from isopropyl alcohol-ether.

Analysis:

calculated:

% C, 64.26;% H, 8.39;% N, 8.33%

% C, 64.32;% H, 8.68;

Example 3

Preparation of DL-2-methyl-5-di-n-propylamino-4,5,6,7-tetrahydro-2H-benzo [c] pyrrole mmol (680 mg) DL-5-di (n-propyl) amino-4 Dissolve 5,6,7-tetrahydro-2H-benzo [c] pyrrole * in 75 ml of dimethylacetamide (DMA), add 10 mmol (1.1 g) of potassium tert-butoxide and stir the mixture for 20 minutes under an atmosphere. A solution of 2.1 mmol of methylpodide (0.13 ml) in 5 ml of domethylformamide was added dropwise, and the reaction mixture was stirred at room temperature for 5 hours, then an additional 0.13 ml of methyl iodide was added and the reaction stirred for a further 3. The reaction mixture was then diluted with water and the aqueous phase was extracted with ethyl acetate, the ethyl acetate phase was separated and washed with water and then with a saturated aqueous sodium chloride solution, and the ethyl acetate layer was dried and evaporated. using ether as the eluent The layers containing DL-2-methyl-5-di-n-propylamino-4,5,6,7-tetrahydro-2H-benzo [c] pyrrole were combined and the solvent was evaporated in vacuo. The NMR spectrum of the residue thus obtained shows the preparation of DL-2-methyl-5-di-n-propylamino-4,5,6,7-tetrahydro-2 H -benzophenylpyrrole.

As evidence of the utility of the compounds of Formula I for the treatment of Parkinson's syndrome, these compounds have been found to affect the rotational behavior in a test using rats injured with 6-hydroxydopamine. Injured rats prepared according to the procedure of Ungerstedt and Arbuthnott, Brain Res. 24, 485 (1970). Compounds having dopamine agonist activity cause rats to rotate in circles against the wound side after injection. After a latency time that is different for different compounds, the rotational speed is measured over a 15 minute period. Compounds are dissolved in water and the aqueous solution is injected rats intraperitoneally at a dose of 1 mg / kg. DL-5-di- (n-propyl) amino-4,5,6,7-tetrahydro-2H-benzo [c] pyrrole maleate provides an average of 34 revolutions per rat, with 1/3 rats exhibiting a rotational behavior that is higher in this test.

The compounds of formula I are also useful as prolactin inhibitors and as such can be used in the treatment of inappropriate lactation such as post-natal lactation and galactorrhea. As evidence of utility in the treatment of diseases in which it is desirable to reduce the prolactin level in mammals, the compounds of Formula I were tested for inhibition of prolactin as follows:

Adult male Sprague-Dawley rats weighing about 200 g are placed in an air-conditioned room with controlled lighting (light from 6 am to 8 pm). and give access to laboratory food and water ad libitum. Each rat was injected intraperitoneally with 2.0 mg of reserpine in aqueous suspension 18 hours prior to isoindole application. Reserpine is administered to ensure that the level of prolactin is uniformly increased. Test compounds are dissolved in water and injected intraperitoneally

Each compound is administered in each dose to a group of 10 rats and a control group of 10 rats is treated with an equivalent amount of solvent. One hour after treatment, all rats are killed by shearing their heads and 150 μΐ serum is tested for prolactin.

The difference between the treated rat prolactin level and the control rat prolactin level divided by the control rat prolactin level indicates the percent inhibition of prolactin secretion determined for the compounds of Formula I. These percentages of inhibition are shown in Table I below. The table in column 1 shows the name of the compound and columns 2 to 4 show the percentage of inhibition of prolactin at the indicated dose.

doses ranging from 5 mg / kg to 50 µg / kg.

Table 1 compound name percent inhibition of prolactin at the indicated dosage level

5 mg / kg 500 / zg / kg 50 pg / k; DL-5-di- (n-propylamino-4,5,6,7-tetrahydro-2H-1-benzo [c] pyrrole maleate 91 47 20 May DL --- diethylamino-4,5,6,7-etrahydro-2H- -benzo [c] pyrrole maleate 23 25

When using compounds of formula I for inhibiting prolactin secretion or for treating Parkinson's syndrome or for other pharmacological purposes, the aforementioned pharmaceutically active compound of formula I or a salt thereof is administered to a person suffering from Parkinsonism or in need of reducing prolactin levels in an amount effective to remove any of symptoms of Parkinsonism or to reduce elevated levels of prolactin. Oral administration is preferred. When parenteral administration is used, injection is performed subcutaneously using appropriate pharmaceutical formulations. Equally effective as parenteral administration is intraperitoneal, intramuscular or intravenous administration. In particular, for intravenous or intramuscular administration, a water-soluble pharmaceutically acceptable salt is used. For oral administration, the pharmaceutically active compound of formula I, either in free base or salt form, can also be mixed with a standard pharmaceutical carrier and filled into empty telescopic gelatin capsules or compressed into tablets. The oral dose range is from 0.01 to 10 mg / kg body weight of the mammal and the parenteral dose range is from 0.0025 to 2.5 mg / kg body weight of the mammal. Intraperitoneal doses ranging from 10 to 30 mg / kg DL-5-di (n-propyl) amino- _4,5 5,6,7-tetrahydrobenzo [2H] pyrrole maleate and do not cause death in mice, but doses of 100 to 300 mg / kg they are already deadly. Some non-toxic side effects were observed at 30 mg / kg.

Claims (4)

SUBJECT A process for the preparation of tetrahydro-2H-benzo [c] pyrrole of general formula I OF THE INVENTION therefor, characterized in that DL-5-amino-4,5,6,7-tetrahydro-2H-benzo [c] pyrrole of formula V γ-NH _z HN— (IN) where R1 is hydrogen or methyl, Am is a substitution N (R ² ) 2 wherein R 2 is methyl, ethyl or n-propyl and reacted with a saturated aldehyde having 1 to 3 carbon atoms and then reduced with an alkali metal hydride to give a compound of formula I wherein R ¹ is hydrogen and Am is N (R ² ') 2, wherein R ² is as defined above, whereupon the product obtained is reacted with a methyl halide and a base to optionally convert to a compound of formula I wherein R ¹ is methyl and Am is N (R2) 2, wherein R2 is as defined above, and optionally converted compounds of formula (I) to their pharmaceutically acceptable salts. 2. Process according to claim 1 for the preparation of DL-5-diethylamino-4,5,6,7-tetrahydro-2H-benzo [c] pyrrole, characterized in that DL-5-amino-4,5,6,7 - Tetrahydro-2H-benzo [c] pyrrole is reacted with acetaldehyde and sodium cyanoborohydride. 3. A process according to claim 1 for the preparation of DL-5-di-n-propylamino-4,5,6,74-tetrahydro-2H-benzo [c] pyrrole, characterized in that DL-5-amino-4,5 is reacted. 6,7-tetrahydro-2H-benzo [c] pyrrole with propionaldehyde and sodium cyanoborohydride. 4. A process according to claim 1 for the preparation of DLt2-methyl-5-di-propylamino-4,5,6,7-tetrahydro-1,2H-benzo [c] pyrrole, characterized in that DL-5-amino-1,4 ₍ 5,6 ₎ is reacted. 7-tetrahydro-2H-benzo [c] pyrrole with propionaldehyde and sodium cyanoborohydride and then methyl iodide.